Prostaglandin analogs

ABSTRACT

Compounds comprising 
                         
or a pharmaceutically acceptable salt or a prodrug thereof is disclosed herein. A, X, J, and E are as described herein. These compounds are useful for treating diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a national stage application under 35 U.S.C. § 371 of PCTapplication PCT/US2005/019408, filed on May 31, 2005, which claims thebenefit of Provisional Application No. 60/585,142, filed on Jul. 2,2004.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds which are useful as therapeuticagents. Among other potential uses, these compounds are believed to haveproperties which are characteristic of prostaglandins.

2. Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last two decades shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et. al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et al., Prodrug 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2α) and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of United States patents assigned to Allergan, Inc.prostaglandin esters with increased ocular hypotensive activityaccompanied with no or substantially reduced side-effects are disclosed.Some representative examples are U.S. Pat. No. 5,446,041, U.S. Pat. No.4,994,274, U.S. Pat. No. 5,028,624 and U.S. Pat. No. 5,034,413 all ofwhich are hereby expressly incorporated by reference.

BRIEF DESCRIPTION OF THE INVENTION

A compound comprising

-   or a pharmaceutically acceptable salt or a prodrug thereof, is    disclosed herein;-   wherein a dashed line represents the presence or absence of a double    bond or a triple bond;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O;-   X is selected from the group consisting of CO₂H, CONHR₂, CONR₂,    CON(OR)R, CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,    CONHSO₂R, SO₂NR₂, SO₂NHR, and

-   J is C═O, CHOH, or CH₂CHOH;-   R is independently H, C₁-C₆ alkyl, phenyl, or biphenyl; and-   E is C₃-C₆ alkyl, C₄-C₁₀ cycloalkyl, phenyl or napthyl having from 0    to 2 substituents, or a heteroaromatic moiety having from 0 to 2    substituents, wherein said substituents comprise up to 4    non-hydrogen atoms.

Methods of treating certain conditions or diseases, and compositions andmedicaments related thereto are also contemplated.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

Schemes 1-3 illustrate three methods of preparing the compoundsdisclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

While not intending to limit the scope of the invention in any way,compounds comprising

pharmaceutically acceptable salts, or prodrugs thereof, are useful forthe purposes disclosed herein.

While not intending to limit the scope of the invention in any way,compounds having the stereochemistry indicated in the structure belowmay be particularly useful.

Pharmaceutically acceptable salts or prodrugs of compounds of thestructure above are also considered to be particularly useful.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

In relation to the identity of A disclosed in the chemical structurespresented herein, in the broadest sense, A is —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms maybe substituted with S or O. In other words, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, —CH₂C≡C—(CH₂)₃—, or A may be a group which is relatedto one of these three moieties in that any carbon is substituted with Sor O. For example, while not intending to limit the scope of theinvention in any way, A may be an S substituted moiety such as one ofthe following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be an O substituted moiety such as one of thefollowing or the like.

In certain compounds A is —(CH₂)₄OCH₂—, —CH₂CH═CHCH₂OCH₂—, or—CH₂C≡CCH₂OCH₂—, that is they can be generically described by thestructure shown below.

Pharmaceutically acceptable salts and prodrugs thereof are alsocontemplated.

In other embodiments, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃— having no heteroatom substitution, that is they can begenerically described by the structure shown below.

Pharmaceutically acceptable salts and prodrugs thereof are alsocontemplated.

While not intending to limit the scope of the invention in any way,compounds according to the structures below are specificallycontemplated.

Pharmaceutically acceptable salts or prodrugs of compounds of thesestructures are also contemplated.

E can vary broadly, as E may be C₃-C₆ alkyl, C₄-C₁₀ cycloalkyl, phenylor napthyl having from 0 to 2 substituents, or a heteroaromatic moietyhaving from 0 to 2 substituents, wherein said substituents comprise upto 4 non-hydrogen atoms.

Thus, E may be C₃-C₆ alkyl, including linear alkyl such as n-propyl,n-butyl, n-penyl, or n-hexyl; branched alkyl such as iso-propyl,iso-butyl and other branched butyl isomers, iso-pentyl and otherbranched pentyl isomers, and the branched hexyl isomers. E may also beC₄-C₁₀ cycloalkyl, including cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl; cycloalkyl withlinear or branched substituents are also considered cycloalkyl such asmethylcyclohexyl, methylcyclobutyl, ethylcyclohexyl and the like. Acycloalkyl ring may also be attached the remainder of the molecule via alinear or branched alkyl fragment, such as for example, the followingmoieties

and the attaching fragment as well as the cyclic part is considered tobe the entire cycloalkyl moiety. Additionally, any other hydrocarbonmoiety which can be conceived by a person of ordinary skill in the artwhich consists of a cycloalkyl ring in any form with any othercombination of linear or branched alkyl groups is a cycloalkyl moiety.

E may also be phenyl or naphthyl having from 0 to 2 substituents.

E may also be a heteroaromatic moiety having from 0 to 2 substituents.

The substituents comprise up to 4 non-hydrogen atoms, in other words,there are from 1 to 4 atoms which are not hydrogen, and any number ofhydrogen atoms required to form the complete substituent. For example, amethyl substituent has 1 carbon atom and 3 hydrogen atoms. Other examplesubstituents include hydrocarbon moieties comprising from 1 to 4 carbonatoms including alkyl such as ethyl, propyl, isopropyl, and butyl andisomers thereof; cyclic and unsaturated hydrocarbons having from 2 to 4carbon atoms such as ethylenyl, propenyl, propynyl, cyclopropyl,cyclobutyl, etc; CO₂H and salts thereof; alkoxy up to C₃ such asmethoxy, ethoxy, propoxy, isopropoxy, and the like; carboxylic acidesters; CN; NO₂; CF₃; F; Cl; Br; I; sulfonyl esters; SO₃H and saltsthereof; and the like. Thus, for example, E may be phenyl, a naphthyl,or a heteroaromatic moiety such as thienyl, furyl, pyridinyl,benzothienyl, benzofuryl, and the like, having no substituents.Alternatively the aromatic or heteroaromatic moiety may bemonoalkylsubstituted moiety such as methylphenyl, ethylbenzofuryl,propylthienyl, etc.; a monohalosubstituted moiety such as fluorophenyl,chlorofuryl, bromopyridinyl, etc.; or a monosubstituted aromatic moietywith another substituent having less than 4 non-hydrogen atoms. Thearomatic or heteroaromatic moiety may also be a disubstituted moeityhaving the same or different substituents. These substituents may be inany reasonable position on the aromatic or heteroaromatic ring.

J is C═O, CHOH, or CH₂CHOH, meaning that the following types ofcompounds, or pharmaceutically acceptable salts or prodrugs thereof, arecontemplated.

In other compounds, X is CO₂H, as depicted in the structure below.

Pharmaceutically acceptable salts and prodrugs of compounds representedby the structure above are also contemplated.

Thus, while not intending to limit the scope of the invention in anyway, the compounds shown below, and pharmaceutically acceptable saltsand prodrugs thereof, are of interest.

For compounds characterized by the phrases “X is CO₂H” or the like,where the group could be converted to a pharmaceutically acceptablesalt, or where a derivative of the group would make the compound aprodrug, a term for a group such as “CO₂H” or “NH” is intended to meanthe actual group, the pharmaceutically salts, or the derivatives of thegroup which make the compound a prodrug.

While not intending to limit the scope of the invention in any way,other compounds of particular interest herein are those of thestructures shown below, and pharmaceutically acceptable salts andprodrugs thereof.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

While not intending to limit the scope of the invention in any way,examples of prodrugs of the useful compounds disclosed herein includethose shown below.

The tetrazole group,

has two tautomeric forms, which can rapidly interconvert in aqueous orbiological media, and are thus equivalent to one another. The tautomerof the tetrazole shown above is shown below.

For the purposes disclosed herein, all tautomeric forms should beconsidered equivalent in every way.

The compounds disclosed herein are useful for the prevention ortreatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds ispreferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid composition which is formulated for topical ophthalmic use isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort. In the case that comfort cannot be maximized, theliquid should be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuricnitrate. A useful surfactant is, for example, Tween 80. Likewise,various useful vehicles may be used in the ophthalmic preparationsdisclosed herein. These vehicles include, but are not limited to,polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant includes,but is not limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs are contemplated:

-   βBlockers (or β-adrenergic antagonists) including carteolol,    levobunolol, metiparanolol, timolol hemihydrate, timolol maleate,    β1-selective antagonists such as betaxolol, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   Adrenergic Agonists including-   non-selective adrenergic agonists such as epinephrine borate,    epinephrine hydrochloride, and dipivefrin, and the like, or    pharmaceutically acceptable salts or prodrugs thereof; and-   α₂-selective adrenergic agonists such as apraclonidine, brimonidine,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Carbonic Anhydrase Inhibitors including acetazolamide,    dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the    like, or pharmaceutically acceptable salts or prodrugs thereof;-   Cholinergic Agonists including-   direct acting cholinergic agonists such as carbachol, pilocarpine    hydrochloride, pilocarbine nitrate, pilocarpine, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   chlolinesterase inhibitors such as demecarium, echothiophate,    physostigmine, and the like, or pharmaceutically acceptable salts or    prodrugs thereof;-   Glutamate Antagonists and other neuroprotective agents such as Ca²⁺    channel blockers such as memantine, amantadine, rimantadine,    nitroglycerin, dextrophan, detromethorphan, CGS-19755,    dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil,    diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related    drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine,    2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine,    barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Prostamides such as bimatoprost, or pharmaceutically acceptable    salts or prodrugs thereof; and-   Prostaglandins including travoprost, UFO-21, chloprostenol,    fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone,    latanoprost and the like.-   Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940    and the like, or pharmaceutically acceptable salts or prodrugs    thereof.-   For treatment of diseases affecting the eye including glaucoma,    these compounds can be administered topically, periocularly,    intraocularly, or by any other effective means known in the art.

Treatment of inflammatory bowel disease may be accomplished by theadministration of the compounds described herein to the sufferingmammal. Inflammatory bowel disease describes a variety of diseasescharacterized by inflammation of the bowels including, but not limitedto, ulcerative colitis and Crohn's disease. Treatment may beaccomplished by oral administration, by suppository, or parenteraladministration, or some other suitable method.

For the treatment of inflammatory bowel disease and similar disorders,the compounds disclosed herein may be used in combination with othertherapeutically active agents.

For the treatment of inflammatory bowel disease, combination treatmentwith the following classes of drugs are contemplated:

-   aminosalicylates including sulfasalazaline, mesalazine,    sulfasalazine, mesalamine, Olsalazine, balsalazide-   corticosteroids including methotrexate, cortisone, hydrocortisone,    prednisone, prednisolone, methylprednisone, triamcinolone,    fluoromethalone, dexamethasone, medrysone, betamethasone,    loteprednol, fluocinolone, flumethasone, or mometasone-   immunomodulators including azathioprine, 6-mercaptopurine,    cyclosporine, and the like.

While not intending to limit the scope of the invention in any way,delivery of the compounds disclosed herein to the colon via oral dosageforms may be accomplished by any of a number of methods known in theart. For example, reviews by Chourasia and Jain in J Pharm PharmaceutSci 6 (1): 33-66, 2003 and Shareef et. al (AAPS PharmSci 2003; 5 (2)Article 17) describe a number of useful methods. While not intending tolimit the scope of the invention in any way these methods include 1)administration of a prodrug, including an azo or a carbohydrate basedprodrug; 2) coating the drug with, or encapsulating or impregnating thedrug into a polymer designed for delivery to the colon, 3) time releaseddelivery of the drug, 4) use of a bioadhesive system; and the like.

While not intending to be bound in any way by theory, it is believedthat intestinal microflora are capable of reductive cleavage of an azobond leaving the two nitrogen atoms as amine functional groups. Whilenot intending to limit the scope of the invention in any way, the azoprodrug approach has been used to deliver to 5-aminosalicylic acid tothe colons of humans in clinical trials for the treatment ofinflammatory bowel disease. It is also believed that bacteria of thelower GI also have enzymes which can digest glycosides, glucuronides,cyclodextrins, dextrans, and other carbohydrates, and ester prodrugsformed from these carbohydrates have been shown to deliver the parentactive drugs selectively to the colon. For example, in vivo and in vitrostudies on rats and guinea pigs with prodrugs of dexamethasone,prednisolone, hydrocortisone, and fludrocortisone, suggest thatglycoside conjugates may be useful for the delivery of steroids to thehuman colon. Other in vivo studies have suggested that glucouronide,cyclodextrin, and dextran prodrugs of steroids or non-steroidalanti-inflammatory drugs are useful for delivery of these drugs to thelower GI tract. An amide of salicylic acid and glutamic acid has beenshown to be useful for the delivery of salicylic acid to the colon ofrabbit and dog.

While not intending to limit the scope of the invention in any way,carbohydrate polymers such as amylase, arabinogalactan, chitosan,chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, orazo-group containing polymers can be used to coat a drug compound, or adrug may be impregnated or encapsulated in the polymer. It is believedthat after oral administration, the polymers remain stable in the upperGI tract, but are digested by the microflora of the lower GI thusreleasing the drug for treatment.

Polymers which are sensitive to pH may also be used since the colon hasa higher pH than the upper GI tract. Such polymers are commerciallyavailable. For example, Rohm Pharmaceuticals, Darmstadt, Germany,markets pH dependent methacrylate based polymers and copolymers whichhave varying solubilities over different pH ranges based upon the numberof free carboxylate groups in the polymer under the tradename Eudragit®.Several Eudragit® dosage forms are currently used to deliver salsalazinefor the treatment of ulcerative colitis and Crohn's disease. Timerelease systems, bioadhesive systems, and other delivery systems havealso been studied.

EXAMPLE 1

Preparation of the seven-membered lactam structure such as that shown inScheme 1 may be accomplished according to a number of publishedprocedures.

The U.S. Pat. No. 6,747,037 and United States Patent Applicationentitled “Piperidinyl Prostaglandin E Analogs”, Filed Jun. 3, 2004, inthe name of inventors David W. Old and Danny T. Dinh (hereafter referredto as the Ser. No. 10/861,957), both of which are expressly incorporatedby reference herein, disclose a method for cyclizing amino acid esterssuch as 2-aminoadipic acid diethyl ester by heating the compound. By asimilar procedure, 2-aminopimelic acid diethyl ester in Scheme 1 isheated and purified according to routine procedures to produce thecyclic 7-oxo-azepane-2-carboxylic acid ethyl ester in Scheme 1.

Alternatively, Almstead et. al. (J. Med. Chem., 42 (22), 4547-4562)discloses a procedure for preparing7-Carbomethoxy-tetrahydro-2(3H)-azepinone as follows:

-   -   “Ethyl 2-cyclohexanonecarboxylate (15.0 g, 88.12 mmol) was        dissolved in chloroform (200 mL) and cooled to 0° C.        Methanesulfonic acid (84.7 g, 881.2 mmol) was added followed by        the addition of sodium azide. The reaction mixture was stirred        at room temperature for 30 min and then heated to reflux for        5 h. Ice was added to the reaction mixture and the resulting        solution was stirred for several minutes. Ammonium hydroxide was        added until the reaction was made basic. The mixture was        extracted with methylene chloride, and the organic layers were        dried (MgSO₄) and concentrated under reduced pressure to an        oil.”        7-Carbomethoxy-tetrahydro-2(3H)-azepinone may be used to prepare        compounds disclosed herein using the synthesis described in the        Ser. No. 10/861,957 or similar methods known in the art. Aspects        of this synthesis are also summarized in Scheme 2.

Alternatively, a method such as the one depicted in Scheme 3 could beused. In this method, a hydroxyl group-containing cyclic ketone isoximated, and the oximated product is then subjected to Beckmannrearrangement to obtain the ring-enlarged lactam according to aprocedure described in detail in JP 05086034. The compounds disclosedherein are then prepared from this compound using the methods of theSer. No. 10/861,957 or similar methods known in the art.

Binding Data Functional Data (EC50 in nM) Structure hEP2 hEP4 hFP hEP1hEP2 hEP3A hEP4 hTP hIP hDP

NA >10000

NA NA >10000

NA NA NA NA 3082 NA NA NA

NA NA NA NA NA 1225 278 NA NA

NA >10000

NA >10000

NA NA NA >10000 3282 NA NA NA

NA NA NA NA 451 549 1636 NA

NA >10000

NA NA NA NA 2386 41 NA NA

NA >10000

NA NA NA NA 2001 112 NA NA

NA NA

NA >10000

NA >10000

NA NA

NA >10000

NA NA

NA >10000

NA >10000

NA NA

NA NA

NA >10000

NA NA NA NA 266 221 NA NA

NA >10000 NA NA NA NA 13262 NA NA NA

NA NA NA NA >10000 NA NA

NA NA NA NA 2143 NA NA NA

NA >10000 NA NA NA NA 116 NA NA

The biological activity of the compounds of Table 1 were tested usingthe following procedures.

Radioligand Binding

Cells Stably Expressing EP₁, EP₂, EP₄ and FP Receptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors are washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer is added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

The cell homogenate is centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet is resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [³H-]17-phenylPGF_(2□)(5 nM) are performed in a 100 μl volume for 60 min. Bindingreactions are started by adding plasma membrane fraction. The reactionis terminated by the addition of 4 ml ice-cold TRIS-HCl buffer and rapidfiltration through glass fiber GF/B filters using a Brandel cellharvester. The filters are washed 3 times with ice-cold buffer and ovendried for one hour.

[³H-] PGE₂ (specific activity 180 Ci mmol) is used as the radioligandfor EP receptors. [³H] 17-phenyl PGF_(2□)is employed for FP receptorbinding studies. Binding studies employing EP₁, EP₂, EP₄ and FPreceptors are performed in duplicate in at least three separateexperiments. A 200 μl assay volume is used. Incubations are for 60 mm at25° C. and are terminated by the addition of 4 ml of ice-cold 50 mMTRIS-HCl, followed by rapid filtration through Whatman GF/B filters andthree additional 4 ml washes in a cell harvester (Brandel). Competitionstudies are performed using a final concentration of 5 nM [³H]-PGE₂, or5 nM [³H] 17-phenyl PGF_(2□)and non-specific binding determined with10⁻⁵M of unlabeled PGE₂, or 17-phenyl PGF_(2□), according to receptorsubtype studied.

Methods for FLIPR™ Studies

(a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hIP; hTP), are cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcium Signal Studies On the FLIPR™

Cells are seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells are then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates are washed four timeswith HBSS-HEPES buffer to remove excess dye leaving 100 μl in each well.Plates are re-equilibrated to 37° C. for a few minutes.

Cells are excited with an Argon laser at 488 nm, and emission ismeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution is added in a 50 μlvolume to each well to give the desired final concentration. The peakincrease in fluorescence intensity is recorded for each well. On eachplate, four wells each serve as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α), (hFP); carbacyclin(hIP); U-46619 (hTP), depending on receptor). The peak fluorescencechange in each drug-containing well is then expressed relative to thecontrols.

Compounds are tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate are examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate are tested in duplicates in a concentration range between 10⁻⁵ and10⁻¹¹ M. The duplicate values are averaged. In either, HTS or CoReformat each compound is tested on at least 3 separate plates using cellsfrom different passages to give an n≧3.

The results of these assays will demonstrate that the compoundsdisclosed herein have activity characteristic of prostaglandins, andwill thus be useful in treating diseases such as glaucoma which areamenable to treatment by prostaglandins.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound having a formula:

or a pharmaceutically acceptable salt or a C₁₋₆ alkyl ester prodrugthereof; wherein a dashed line represents the presence or absence of adouble bond or a triple bond; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; X is selected from the group consisting of CO₂H, CONHR₂, CONR₂,CON(OR)R, CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R,SO₂NR₂, SO₂NHR, and

J is C═O, CHOH, or CH₂CHOH; R is independently H, C₁-C₆ alkyl, phenyl,or biphenyl; and E is C₃-C₆ alkyl, C₄-C₁₀ cycloalkyl, phenyl or napthylhaving from 0 to 2 substituents, or thienyl, furyl, pyridinyl,benzothienyl, or benzofuryl having from 0 to 2 substituents, whereinsaid substituents are independently selected from: a hydrocarbon moietyhaving from 1 to 4 carbon atoms, CO₂H, alkoxy having from 1 to 3 carbonatoms, CN, NO₂, CF₃, F, Cl, Br, I, and SO₃H.
 2. The compound of claim 1having a formula:

or a pharmaceutically acceptable salt or a prodrug thereof.
 3. Thecompound of claim 1 having a formula:

or a pharmaceutically acceptable salt or a prodrug thereof.
 4. Thecompound of claim 3 wherein J is C═O.
 5. The compound of claim 3 whereinJ is CHOH.
 6. The compound of claim 3 wherein X is CO₂H.
 7. The compoundof claim 3 wherein E is phenyl, thienyl, furyl, pyridinyl, napthyl,benzothienyl, or benzofuryl having from 0 to 2 substituents.
 8. Thecompound of claim 3 wherein E is n-butyl.
 9. The compound of claim 1having a formula:

or a pharmaceutically acceptable salt or a prodrug thereof.
 10. Thecompound of claim 1 having a formula:

or a pharmaceutically acceptable salt or a prodrug thereof.
 11. Thecompound of claim 1 having a formula:

or a pharmaceutically acceptable salt or a prodrug thereof.
 12. A liquidcomposition comprising the compound according to claim 1 and apharmaceutically acceptable excipient, wherein said liquid is formulatedfor ophthalmic use.
 13. A method of treating glaucoma or ocularhypertension comprising administering a compound of claim 1 to a mammal.